DESCRIPTION: (Applicant's abstract) Previous studies utilizing animal models of Huntington's disease (HD) have demonstrated that excitotoxicity mediated by neurotransmitter receptors can be correlated to specific change in the brain which mimic HD neuropathology. Also, changes in the expression of specific neurotransmitter receptors have been observed in actual HD cases. Recently, we have discovered that a mouse model of HD transgenic for exon 1 of the disease gene, huntintin, demonstrates aberrancies in selected glutamate, dopamine and adenosine receptor expression prior to the onset of disease symptoms. Thus, we have hypothesized that dysregulation of neurotransmitter receptor gene expression may be a key mechanism by which the mutant huntintin effects neurologic insult. I propose to explore this hypothesis using newly developed RNA analysis methodologies (antisense RNA amplification together with reverse northern blotting and differential display) to examine changes in gene expression at the single-cell level in animal and cell culture HD models and in autopsy material from HD patients. Elucidation of the process by which the expression of mutant huntintin may result in cell dysfunction and death may afford new opportunities for therapeutic intervention in HD.